The long term objectives of this grant are to understand the regulation of the early events in neuronal differentiation and the mechanisms underlying the formation of specific axonal connections as they are exemplified by the mammalian olfactory system. The olfactory system is particularly well-suited for studying issues in developmental neurobiology because of the unique ability of the primary olfactory neurons to be replaced if they die by newly born neurons whose differentiation in adult animals mimics the events of early neurogenesis. Indeed, olfactory neurons have several phenotypic characteristics in common with neuronal precursors and immature neurons elsewhere in the CNS and PNS. One of the specific aims of this grant is to study why and how these juvenile markers are retained by the olfactory neurons and specifically the influence of the cellular environment on olfactory neuron phenotype. A second aim of this grant relates to the expression of a cell surface marker by a spatially restricted subset of olfactory neurons. The regulation of this positional marker will be studied during the development and the regeneration of the olfactory epithelium. In addition, the function of this protein in axonal growth and synaptogenesis will be assessed through the use of antibody blocking experiments in vitro and in vivo. A third aim of the grant is to ascertain whether the reinnervation of the bulb is anatomically specific following the cycle of epithelial degeneration and then regeneration. These lines of investigation should help provide some insight into the early stages of neuronal development. In addition, they may help to explain how olfactory neurons retain the capacity to functionally reinnervate the CNS, while other neurons do not. As such, this work is directly applicable to our understanding of the limits of neuronal regeneration after nervous system injury.